The present invention relates to a method for increasing bone mineralization in a pediatric population. Other aspects of the invention relate to methods for improving the nutritional status of infants and toddlers.
Bone serves an important physiologic role. It provides mechanical strength. All of the bones collectively, need to be strong enough to support the entire weight of the body, and any additional mechanical burden. It is widely accepted that bone mineral content and density, are directly correlated with the mechanical strength of the bone.
Bone is composed primarily of matrix proteins and calcium salts. Bone growth involves not only an increase in bone size, but an increase in the amount of such components as well. Bone growth is controlled by osteoblasts. These osteoblasts adhere to the terminal portion of existing bone and secrete bone matrix proteins, which differentiate into bone cells (osteocytes) and become part of the tissue of the bone. These osteoid tissues are then mineralized, primarily by calcium and phosphorus. The mineralization gives the bone its mechanical strength and allows it to serve its physiologic role. Substantial bone growth continues for up to the first 20 years of life.
However, after age 35, bone mass and mineral content begin declining gradually reducing the strength of the bone tissue. Consequently, when mechanical strength declines to a certain level, the individual is at greater risk of bone fracture. This is often referred to as osteoporosis.
Medical research has focused on ways of preventing the occurrence of osteoporosis. This research has shown that one of the most effective means of preventing osteoporosis is the establishment of a high bone mass during the childhood years. The establishment of significant bone mass allows a greater loss of bone before osteoporosis becomes problematic. Investigators have started to study childhood diets and their impact on bone formation. Consumption of calcium is an important dietary variable in promoting the development of substantial bone mass in the individual.
Part of this research has examined what impact, if any, infant formula has on bone development. Nelson et al, Journal of the American College of Nutrition, Vol. 17, No. 4, 327-332 (1998), evaluated whether the fatty acid content of infant formula impacted calcium absorption. Nelson et al determined that oil blends did have an impact on calcium absorption. Nelson et al found that the presence of palm olein oil reduced calcium absorption by approximately 35%, when compared to formula which did not contain palm olein oil. The authors concluded that this reduced calcium absorption was unlikely to have any significant physiologic impact on the infant, including bone mineralization. The authors stated that the most likely adverse effect is constipation in the infant.
Nelson et al also evaluated the impact of palm olein on calcium absorption in a different group of infants Am J Clin Nutr 1996;64:291-6 (1996). The results obtained in this study were consistent with the results described by Nelson et al supra. Infants consuming formula containing palm olein oil had lower rates of calcium absorption. The authors emphasized that the clinical significance of such reduced absorption is unknown.
Motil commented on the work of Nelson et al supra, in the Journal of the American College of Nutrition, Vol. 17, No. 4, 303-305 (1998). Motil reiterated that Nelson et al had documented that infants consuming palm olein oil had lower relative calcium absorption, when compared to a group of infants consuming alternative fats. However Motil emphasized that these findings were insignificant from a clinical standpoint. Motil emphasized that calcium homeostasis is a highly regulated process and is not dependent solely upon the amount of calcium that is absorbed. Further, infants in the palm olein group were receiving 100 mg/day of calcium, which is the established RDA. Thus, a fair reading of Motil is that the presence of palm olein is expected to have no impact upon the rate of bone mass development in an infant.
Kennedy et al evaluated an infant formula which contained a synthetic triglyceride (STG) Am J Clin Nutr 1999:70:920-7. This STG contained palmitic acid in the sn-2 position of the glycerol nucleus (i.e. the center carbon atom). This STG is structurally similar to the triglyceride contained in human breast milk. An infant formula containing this STG was compared against a formula containing triglycerides, in which the palmitic acid was contained primarily in the 1- and 3-positions of the glycerol nucleus. These triglycerides are typically contained in infant formula and are obtained from vegetable oils. Kennedy et al evaluated growth rates, fat absorption, and bone mineralization of the two groups. Similar parameters were observed in a group of infants consuming breast milk. Kennedy found that infants consuming the STG had rates of bone mineralization comparable to the breast fed group. Infants receiving the triglycerides obtained from vegetable oils had lower rates of bone mineralization than infants consuming the STG.
Kennedy noted that enhanced calcium absorption had previously been observed with formulae having reduced palmitate content. However, the fatty acid profile of such formula differs substantially from that of breast milk and therefore caution should exercised in its consumption. Kennedy emphasized that palmitic acid is the predominant fatty acid in human milk and the clinical significance of omitting this fatty acid needs further study.
Thus while the prior art clearly establishes that palmitic acid frombovine and vegetable sources negatively impacts the absorption of calcium, the clinical significance of this finding is unknown. Numerous authors agree that the impact of this finding on bone mass is unknown, but probably is clinically insignificant. Other authors suggest caution in the utilization of low palmitic acid formula since it""s fatty acid profile differs so significantly from human milk.
In accordance with the present invention, it has been discovered that it is possible to enhance bone mass accretion in an infant or toddler. This increased bone mass can be accomplished by enterally feeding the juvenile a formula containing a source of calcium and a source of fat, in which the fatty acid profile is characterized by having a palmitic acid content of about 19 w/w %, or less. Such a feeding regimen will result in an enhanced rate of bone mineralization and ultimately enhanced skeletal strength.
The pediatric formula utilized in the method of the present invention will typically be an infant formula. It should contain sufficient nutrients to promote the growth and development of the juvenile. It typically will contain protein, carbohydrate, vitamins, and minerals, as is known in the art. The formula will contain calcium as is known in the art. The key to the invention is the utilization of a fat blend that is low in palmitic acid. While the prior art demonstrates that palmitic acid interferes with the absorption of calcium, the enclosed human clinical studies demonstrate that diminished absorption is associated with decreased levels of bone mass in a human infant. Such a finding contradicts the teachings of the prior art, which taught that this diminished calcium absorption had no clinical significance on bone mass accretion.
The fat blend utilized in the pediatric formula of the present invention must be low in palmitic acid, but yet contain sufficient fatty acids to support optimal infant growth and development. This may be accomplished by a blend having a fatty acid profile characterized by about 9.5-21 weight % lauric acid, about 19 weight %, or less, palmitic acid, and about 34-48 weight % oleic acid. In a further embodiment, palmitic acid content is maintained at about 15 weight %, or less, and often at about 10 weight %, or less. In an additional embodiment, the oil blend may additionally contain about 2.7-3.1 w/w % of stearic acid, about 17-29 w/w % of linoleic acid and about 1.7-3.2 w/w % of linolenic acid. A number of commercially available vegetable oils will produce this profile when blended as described in detail below.
It is believed that enhanced bone mass, continued throughout life, will make individuals less susceptible to osteoporosis when they reach their geriatric years. It is also believed infants consuming this formula will have the opportunity to achieve a greater peak bone mass.
As used in this application, the following terms have the meanings defined below, unless otherwise specified. The plural and the singular should be treated as interchangeable:
1. xe2x80x9cfatty acid profilexe2x80x9d as used herein means the total fatty acid content of the fat, oil, emulsifiers, and other components used to create a pediatric nutritional as determined by conventional analysis. Unless specified otherwise, all percentages are weight percents of total fatty acid content. Those skilled in the art will appreciate that sometimes the levels of fatty acids are reported as grams of fatty acid, per 100 grams of fat.
2. xe2x80x9cincreasing bone mineralizationxe2x80x9d refers to the accumulation of minerals, including calcium and phosphorus, which are deposited in newly formed or remodeled bone matrix.
3. xe2x80x9cinfantxe2x80x9d refers to a child under the age of 1 year.
4. xe2x80x9cjuvenilexe2x80x9d refers to a child under the of age 6, and specifically includes infants, toddlers, etc.
5. Any reference to a numerical range in this application should be construed as an express disclosure of every number specifically contained within that range and of every subset of numbers contained within that range. Further, this range should be construed as providing support for a claim directed to any number, or subset of numbers in that range. For example, a disclosure of 1-10 should be construed as supporting a range of 2-8, 3-7, 5, 6, 1-9, 3.6-4.6, 3.5-9.9, 1.1-9.9, etc.
6. xe2x80x9cpediatric formulaxe2x80x9d as used herein refers to a liquid nutritional designed for infants, toddlers, and juveniles which contains calcium, a fat blend, and optionally nutrients such as protein, vitamin, phosphorus, etc. that are required for growth and development.
The terms xe2x80x9cbone mineralizationxe2x80x9d and xe2x80x9cbone mass accretionxe2x80x9d are being used interchangeably within this application. Thus within the specification or claims, they should be considered as synonyms. xe2x80x9cBone mineralizationxe2x80x9d should also be considered synonymous with increasing, enhancing or improving xe2x80x9cbone strengthxe2x80x9d, xe2x80x9cbone mineral densityxe2x80x9d, xe2x80x9cbone mineral contentxe2x80x9d, xe2x80x9cbone massxe2x80x9d, xe2x80x9cbone accretionxe2x80x9d, etc. Likewise, the terms xe2x80x9cpalm oilxe2x80x9d and xe2x80x9cpalm olein oilxe2x80x9d are also being used as synonyms and should also be considered as interchangeable.
As noted above, the key to the present invention is the discovery that oil blends that inhibit the absorption of calcium produce statistically significant lower rates of bone mass accretion, when compared to oil blends which do not inhibit calcium absorption. Enhanced rates of bone mass accretion can be accomplished by limiting the quantity of palmitic acid contained within the infant formula. Based upon the overall fatty acid profile of the fat composition used in the formula, total palmitic acid content should not exceed about 19 w/w %. Such quantities of palmitic acid do not negatively impact bone mass accretion.
Limiting palmitic acid content in infant formulae goes against traditional wisdom in the field. Most infant formulae makers have attempted to utilize oil blends which create a fatty acid profile that mimics human milk. It is believed that such a profile produces superior growth and development. Palmitic acid typically makes up about 20-25 w/w % of the total fat content in human milk. A comparison of the fatty acid profile of human milk and one of the fatty acid profiles of the invention is listed below in Table I.
The fatty acid profile depicted above can be obtained with a number of vegetable oils that are routinely consumed by infants. These oils include soy, coconut, safflower, high oleic safflower(HOSO), high oleic sunflower (HOSUN), corn, medium chain triglyceride (MCT), palm kernel, palm, and palm olein. The fatty acid profile of each of these oils is listed below in Table II. One skilled in the art understands that a particular fatty acid profile can be obtained by blending different oils, based upon their individual fatty acid profiles, until the desired mix is obtained.
The invention is not limited to the fatty acid profile depicted above in Table I. Alternative fatty acid profiles depicted below in Table III will also produce enhanced rates of bone mass accretion in infants.
The fatty acid profile depicted as xe2x80x9cEmbodiment 1xe2x80x9d as set out above can be accomplished through a blend of about 3850 weight % high oleic safflower oil (HOSO/ or HOSUN), about 26-40 weight % soy oil (SO) and about 22-36 weight % coconut oil (CO).
The fatty acid profile depicted as xe2x80x9cEmbodiment 2xe2x80x9d can be accomplished through a blend of about 41-44 weight % HOSO/HOSUN, about 27-32 weight % SO, and about 27-32 weight % CO. The fatty acid profile depicted as xe2x80x9cEmbodiment 3xe2x80x9d can be accomplished through a blend of about 42 weight % HOSO/HOSUN, about 28 weight % SO and about 30 weight % CO.
As is readily apparent to one skilled in the art, a number of alternative oil blends will provide fatty acid profiles meeting the criteria outlined above in Tables I and ILL. Examples of such oil blends include: those containing admixtures of corn oil, high oleic safflower oil or sunflower oil, MCT oil, safflower oil and coconut oil. More specifically the benefits of the invention can be obtained with an oil blend containing about 0-60 weight % 20 of corn oil, about 20-45 weight % of coconut oil, about 25-60 weight % HOSO or HOSUN, about 0-40 weight % soy oil, about 0-40 weight % safflower oil, and about 0-35% MCT oil, with the proviso that the sum of said fatty acids does not exceed 100 weight %. Alternative blend include those containing from about 20-30 weight % coconut oil, about 45-60 weight % HOSO/HOSUN, and about 10-35% MCT oil. Other embodiments include blends containing 20-55 weight % corn oil, about 20-45 weight % of coconut oil and 25-60 weight % of HOSO/HOSUN. Numerous other variations will be readily apparent to those skilled in the art based upon the fatty acid profiles above and should be considered to be within the scope of the invention.
Other examples of suitable oil blends include: a) about 40% corn, about 20% coconut and about 40% HOSO or HOSUN; b) about 55% corn, about 20% coconut and about 25% HOSO/HOSUN; c) about 20% corn, about 45% coconut, and about 35% HOSO/HOSUN; d) about 40% coconut and about 60% HOSO/HOSUN, and; e) about 20-30% coconut, about 45-60% HOSO/HOSUN, and about 10-35% MCT. Other variations will be readily apparent to one skilled in the art.
High oleic safflower oil (HOSO) refers to oil derived from the seeds of a hybrid safflower plant, Carthamus tinctorius. Safflower oil is an edible oil which typically has a high content of linoleic acid. Hybrids of this plant have been developed which produce a seed oil which has an elevated level of oleic acid. It is the oil that is derived from the seeds of these hybrids which have been found useful in the present invention. Virtually interchangeable with HOSO is high oleic sunflower oil (HOSUN). Like HOSO, higholeic sunflower oil contains an elevated level of oleic acid. When used herein, the term xe2x80x9cHOSOxe2x80x9d includes its sunflower relative.
Soy oil (SO) refers to the fat fraction obtained from the seeds of the legume, Soja max. Typically, the oil fraction of the soya seed undergoes a number of refining, bleaching and deodorization steps resulting in the commercial commodity. Soy oil generally contains relatively high levels of linoleic fatty acid and to a lesser extent, linolenic fatty acid.
Coconut oil (CO) refers to the oil obtained from copra, which is dried coconut meat. This oil is distinguished from HOSO and SO by its high content of saturated, short chain and medium chain fatty acids. Palm kernel oil is very similar in fatty acid profile to CO. When used herein, the term xe2x80x9cCOxe2x80x9d includes its palm kernel relative.
Medium chain triglyceride oil is often referred to as xe2x80x9cfractionated coconut oilxe2x80x9d. As its name implies, it is obtained from coconut oil. Alternatively it may be obtained from palm kernel oil. The coconut oil or palm kernel oil is submitted to chemical purification in order to enrich its relative content ofin saturated fatty acids in the C8-C12 range, especially caprylic(C:8.0) and capric(C:10.0). Techniques for carrying out such enrichments are well known to those skilled in the art.
Numerous commercial sources for the fats listed above are readily available and known to one practicing the art. For example, soy oil is available from Archer Daniels Midland of Decatur, Ill. Corn, coconut, palm and palm kernel oils are available from Premier Edible Oils Corporation of Portland, Organ. Fractionated coconut oil is available from Henkel Corporation of LaGrange, Ill. High oleic safflower and high oleic sunflower oils are available from SVO Specialty Products of Eastlake, Ohio.
In addition to the fat blend, the formula must contain calcium. Infants consuming human breast milk typically consume 250 mg to 330 mg of elemental calcium per day, with a net absorption of between 55-60%. By contrast, infants consuming formula typically consume 500 to 600 mg of elemental calcium per day. The amount of calcium that the infant absorbs is dependant upon the fat content of the formula. Calcium absorption is only about 40% if the formula contains levels of palmitic acid mimicking those of human breast milk. By contrast, the formula of this invention produce calcium absorption in the range of approximately 60%.
The infant formulae of this invention should contain from about 250 mg to about 2000 mg of elemental calcium per liter, and more typically from about 500 mg to about 1000 mg of elemental calcium per liter. Any source of calcium that is appropriate for use in a juvenile population may be utilized in the nutritionals of this invention. Examples of suitable sources of calcium include, but are not limited to, calcium carbonate, calcium chloride, calcium lactate, calcium gluconate, calcium sulfate, calcium phosphate, tricalcium phosphate, calcium citrate, tricalcium citrate, or calcium maleate.
In addition to the calcium and oil blends described above, the pediatric formula of this invention will typically contain protein, carbohydrate, vitamins, minerals, trace minerals, etc. as is known in the art. The specific sources of protein, carbohydrates, vitamins, etc., and their relative quantity, is not critical to the invention and will fit within guidelines typically used in the industry, which is described in greater detail below.
The pediatric formula of the invention may be provided in powered, liquid concentrate or ready-to-feed forms. Before feeding, water is added to both the powdered and concentrate forms of the formula. In a first embodiment, a pediatric formula of the invention comprises, based on a 100 kcal basis, about 8 to about 16 grams carbohydrate (preferably about 9.4 to about 12.3 grams), about 3 to about 6 grams fat (preferably about 4.7 to about 5.6 grams), and about 1.8 to about 3.3 grams of protein (preferably about 2.0 to about 3.3 grams). If provided in a powder form,the formula comprises, based on 100 grams of powder, about 30 to about 90 grams carbohydrate (preferably about 48 to about 59 grams), about 15 to about 30 grams fat (preferably about 22 to about 28), about 8 to about 17 grams protein (preferably about 9 to about 17 grams). A summary of the carbohydrate, fat, and protein ranges (on a per 100 kcal basis, per 100 grams powder basis and per liter basis (as fed concentration) for a formula according to the invention is provided in Table IV.
Suitable carbohydrates, and proteins can vary widely and are well known to those skilled in the art of making pediatric formulas.
One component of the pediatric formulae is a source of carbohydrates. Carbohydrate is a major source of readily available energy that the infant needs for growth and that protects the infant from tissue catabolism. In human milk and most standard milk-based infant formulas, the carbohydrate is lactose.
The carbohydrates that may be used in the formula can vary widely. Examples of carbohydrates suitable for infants include hydrolyzed corn starch, maltodextrin, glucose polymers, sucrose, corn syrup, corn syrup solids, rice derived carbohydrate, glucose, fructose, lactose, high fructose corn syrup and indigestible oligosaccharides such as fructooligosaccharides (FOS). Any single carbohydrate listed above, or any combination thereof, as appropriate may be utilized.
Commercial sources for the carbohydrates listed above are readily available and known to one practicing the art. For example,corn syrup solids are available from Cerestar USA, Inc in Hammond, Ind. Glucose and rice based syrups are available from California Natural Products in Lathrop, Calif. Various corn syrups and high fructose corn syrups are available from Cargil in Minneapolis, Minn. Fructose is available from A. E. Staley in Decatur, Ill. Maltodextrin, glucose polymers, hydrolyzed corn starch are available from American Maize Products in Hammond, Ind. Sucrose is available from Domino Sugar Corp. in New York, N.Y. Lactose is available from Foremost in Baraboo, Wis. and indigestible oligosaccharides such as FOS are available from Golden Technologies Company of Golden, Colo.
The fats used in the formula have been described in detail above. In addition to these vegetable oils, the formula may also contain arachidonic acid, docosahexaneoic acid, and mixtures thereof. Such lipids have been shown to have beneficial effects in infants, including enhanced brain and vision development U.S. Pat. No. 5,492,938 to Kyle et al. describes these effects in greater detail. Lipid sources of arachidonic acid and docosahexaneoic acid include, but are not limited to, marine oil, egg derived oils, and fungal oil. Marine oil is available from Mochida International of Tokyo, Japan.DHA is available from Martek Biosciences Corporation of Columbia, Md. Arachidonic acid is available from Genzyme Corporation of Cambridge, Mass.
The proteins that may be utilized in the pediatric formula of the invention include any proteins or nitrogen source suitable for human consumption. Such proteins are well known by those skilled in the art and can be readily selected when preparing such products. Examples of suitable protein sources include casein, whey, condensed skim milk, nonfat milk, soy, pea, rice, corn, hydrolyzed protein, free amino acids, and mixtures thereof.
Commercial protein sources are readily available and known to one practicing the art. For example, caseinates, whey, hydrolyzed caseinates, hydrolyzed whey and milk proteins are available from New Zealand Milk Products of Santa Rosa, Calif. Soy and hydrolyzed soy proteins are available from Protein Technologies International of Saint Louis, Missouri. Pea protein is available from Feinkost Ingredients Company of Lodi, Ohio. Rice protein is available from California Natural Products of Lathrop, Calif. Corn protein is available from EnerGenetics Inc. of Keokuk, Iowa. Additionally, mineral enriched proteins are available from New Zealand Milk Products of Santa Rosa, Calif. and Protein Technologies International of Saint Louis, Miss.
A formula of the invention preferably also contains vitamins and minerals in an amount designed to supply the daily nutritional requirements of a pediatric population. The formula preferably includes, but is not limited to, the following vitamins and minerals: phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, selenium, iodine, and Vitamins A, E, C, D, K and the B complex. Further nutritional guidelines for infant formulas can be found in the Infant Formula Act, 21 U.S.C. section 350(a). The nutritional guidelines found in the Infant Formula Act continue to be refined as further research concerning infant nutritional requirements is completed. This invention is intended to encompass formulas containing vitamins and minerals that may not currently be listed in the Act.
The pediatric formulas of this invention can be manufactured using techniques well known to those skilled in the art. Various processing techniques exist for producing powdered, ready-to-feed and concentrate liquid formulas. Typically, these techniques include formation of a slurry from one or more solutions which may contain water and one or more of the following: carbohydrates, proteins, lipids, stabilizers, vitamins and minerals. This slurry is emulsified, homogenized and cooled. Various other solutions may be added to the slurry before processing, after processing or at both times. The processed formula is then sterilized and may be diluted to be utilized on a ready-to-feed basis or stored in a concentrated liquid or a powder. If the resulting formula is meant to be a ready-to-feed liquid or concentrated liquid, an appropriate amount of water would be added before sterilization. If the resulting formula is meant to be a powder, the slurry will be heated and dried to obtain a powder. The powder resulting from drying may be dry blended with further ingredients, if desired.
In actual use, the formula of this invention may be consumed by any human. More specifically, the specified fat composition of this invention may be incorporated into a formula which is in compliance with accepted levels of vitamins, minerals, micro-components and the like. The amount consumed does not differ from that associated with the normal consumption of commercially available infant formula. The caloric density (i.e., kcals/ml) and caloric distribution (i.e., the relative proportion of calories from fat, protein and carbohydrate) are not critical to this invention but are generally comparable to conventional formulas. As is well know to those skilled in the art, these factors can vary with the intended use of the formula. For example, preterm, term and toddler infants have somewhat differing caloric density requirements. Also, formulas for specific disease states (e.g., diabetes, pulmonary deficiency, in-born errors of metabolism, and immune comprised) will have differing caloric distributions. Those skilled in the art are aware of these differences and will readily adapt the present invention to meethose special needs.
The invention has been described as a method of enhancing the bone mass of infants, juveniles, children, etc. It should be understood that any human being, regardless of their age, will experience enhanced calcium absorption, with the fat blends of this invention. As a practical matter however, typically only infants and toddlers consume such formula. The invention should be construed as covering any human being who consumes the nutritionals described above.
The following examples are illustrative of the methods and compositions of the invention for enhancing bone mass growth in pediatric patients. While the invention is described in terms of a ready-to-feed infant nutritional formula in the examples, below, it is not intended to be so limited, as it is intended to encompass both powdered and concentrate liquid infant formulas as well as formulas for children one year in age or older. The examples are not intended to be limiting as other carbohydrates, lipids, proteins, stabilizers, vitamins and minerals may be used without departing from the scope of the invention.